Atf6 inhibitors and uses thereof

Abstract

Compounds as inhibitors of Activating Transcription Factor 6 (ATF6) are provided. The compounds may find use as therapeutic agents for the treatment of diseases or disorders mediated by ATF6 and may find particular use in the treatment of viral infections, neurodegenerative diseases, vascular diseases, or cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims prior benefit of U.S. Provisional Patent Application No. 62 / 654,263, filed Apr. 6, 2018, the disclosures of which are hereby incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] This disclosure relates generally to therapeutic agents that may be useful as inhibitors of Activating Transcription Factor 6 (ATF6).BACKGROUND

[0003] Multiple myeloma (MM) remains a predominantly incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. Proteasome inhibitors (PI) such as Bortezomib have increased the response rate and survival of patients with MM. The overall patient response rate of newly diagnosed MM to Bortezomib and Dexamethasone is about 67%. In relapsed refractory MM, the response rate is reduced to about 40-60%. Therefore, there are a significant number of MM patients who are resistant to Bortezomib. MM cells are inherently sensitive to PIs because...

Examples

examples

Synthetic Examples

[0495]The following examples are offered to illustrate but not to limit the present disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (A), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or a salt thereof. The compounds are prepared using the general methods described above.

[0496]The following abbreviations are used throughout the Examples: DCM (dichloromethane), DIAD (diisopropyl azodicarboxylate), DIPEA or DIEA (N,N-diisopropylethylamine), DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HPLC (high-pressure liquid chromatography), IPA (isopropyl alcohol), LCMS (liquid chromatography mass spectrometry), NMR (nuclear magnetic resonance), PPh3 (triphenylphosphane), RT...

example s1

of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)propyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide (Compound 1)

[0497]

[0498]Step 1: Synthesis of 1-(2,4-bis(trifluoromethyl)phenyl)ethan-1-ol. To a stirred solution of 2,4-bis(trifluoromethyl)benzaldehyde (500 mg, 2.06 mmol, 1 equiv) in THF (5 mL) was added ethylmagnesium bromide (412 mg (3 ml), 3.09 mmol, 1.5 equiv) portion wise at rt, and the reaction was stirred for 10 minutes. The reaction mixture was allowed to stir for 1 hour at RT. Product formation was confirmed by TLC & NMR. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with water (50 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 1-(2,4-bis(trifluoromethyl)phenyl)ethan-1-ol. (110 gm, 19% as colourless liquid). 1H NMR (400 MHz, DMSO-d6) δ=8.13-8.06 (m, 1H), 8.05-7.99 (m, 1H), 7.94 (s, 1H), 4.80 (br. s., 1H), 1.65-1...

example s2

of N-(7-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide (Compound 2)

[0502]

[0503]Step 1: Synthesis of 1-(2,4-bis(trifluoromethyl)benzyl)-4-nitro-1H-pyrazole. 4-nitro-1H-pyrazole (0.73 g, 0.006 moles, 1 eq) was taken in DMF (20 mL). Cool this reaction mixture by ice water up to 0° c. add K2CO3 (1.34 g, 0.009 mole, 1.5 eq) portion wise in it stirred reaction mixture for 10 minute and then add 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (2.0 g, 0.006 mole, 1 eq) in it by drop by drop. Stir above reaction mixture for 1 hour (reaction was monitored by TLC & LCMS). After completion of reaction, reaction mixture was diluted with ethyl acetate (50 mL) and extracted with water (50 mL). Collect organic layer and concentrate it to obtain product which further purified by flash chromatography to obtain White color product. LCMS: 339 [M+H]+.

[0504]Step 2: Synthesis of 1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-amine. To a stirred solution ...

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims prior benefit of U.S. Provisional Patent Application No. 62 / 654,263, filed Apr. 6, 2018, the disclosures of which are hereby incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] This disclosure relates generally to therapeutic agents that may be useful as inhibitors of Activating Transcription Factor 6 (ATF6).BACKGROUND

[0003] Multiple myeloma (MM) remains a predominantly incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. Proteasome inhibitors (PI) such as Bortezomib have increased the response rate and survival of patients with MM. The overall patient response rate of newly diagnosed MM to Bortezomib and Dexamethasone is about 67%. In relapsed refractory MM, the response rate is reduced to about 40-60%. Therefore, there are a significant number of MM patients who are resistant to Bortezomib. MM cells are inherently sensitive to PIs because...

Examples

examples

Synthetic Examples

[0495]The following examples are offered to illustrate but not to limit the present disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (A), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik), or a salt thereof. The compounds are prepared using the general methods described above.

[0496]The following abbreviations are used throughout the Examples: DCM (dichloromethane), DIAD (diisopropyl azodicarboxylate), DIPEA or DIEA (N,N-diisopropylethylamine), DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HPLC (high-pressure liquid chromatography), IPA (isopropyl alcohol), LCMS (liquid chromatography mass spectrometry), NMR (nuclear magnetic resonance), PPh3 (triphenylphosphane), RT...

example s1

of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)propyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide (Compound 1)

[0497]

[0498]Step 1: Synthesis of 1-(2,4-bis(trifluoromethyl)phenyl)ethan-1-ol. To a stirred solution of 2,4-bis(trifluoromethyl)benzaldehyde (500 mg, 2.06 mmol, 1 equiv) in THF (5 mL) was added ethylmagnesium bromide (412 mg (3 ml), 3.09 mmol, 1.5 equiv) portion wise at rt, and the reaction was stirred for 10 minutes. The reaction mixture was allowed to stir for 1 hour at RT. Product formation was confirmed by TLC & NMR. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with water (50 mL×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 1-(2,4-bis(trifluoromethyl)phenyl)ethan-1-ol. (110 gm, 19% as colourless liquid). 1H NMR (400 MHz, DMSO-d6) δ=8.13-8.06 (m, 1H), 8.05-7.99 (m, 1H), 7.94 (s, 1H), 4.80 (br. s., 1H), 1.65-1...

example s2

of N-(7-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide (Compound 2)

[0502]

[0503]Step 1: Synthesis of 1-(2,4-bis(trifluoromethyl)benzyl)-4-nitro-1H-pyrazole. 4-nitro-1H-pyrazole (0.73 g, 0.006 moles, 1 eq) was taken in DMF (20 mL). Cool this reaction mixture by ice water up to 0° c. add K2CO3 (1.34 g, 0.009 mole, 1.5 eq) portion wise in it stirred reaction mixture for 10 minute and then add 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (2.0 g, 0.006 mole, 1 eq) in it by drop by drop. Stir above reaction mixture for 1 hour (reaction was monitored by TLC & LCMS). After completion of reaction, reaction mixture was diluted with ethyl acetate (50 mL) and extracted with water (50 mL). Collect organic layer and concentrate it to obtain product which further purified by flash chromatography to obtain White color product. LCMS: 339 [M+H]+.

[0504]Step 2: Synthesis of 1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-amine. To a stirred solution ...

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